Glucocorticoid-induced leucine zipper modulates macrophage polarization and apoptotic cell clearance

被引：30

作者：

Vago, Juliana P. ^{[1
,2
,4
]}

Galvao, Izabela ^{[1
,2
]}

Negreiros-Lima, Graziele L. ^{[3
]}

Teixeira, Livia C. R. ^{[3
]}

Lima, Katia M. ^{[3
]}

Sugimoto, Michelle A. ^{[2
]}

Moreira, Isabella Z. ^{[3
]}

Jones, Sarah A. ^{[4
]}

Lang, Tali ^{[4
]}

Riccardi, Carlo ^{[5
]}

Teixeira, Mauro M. ^{[1
,2
]}

Harris, James ^{[4
]}

Morand, Eric F. ^{[4
]}

Sousa, Lirlandia P. ^{[3
]}

机构：

[1] Univ Fed Minas Gerais, Inst Ciencias Biol, Dept Morfol, Belo Horizonte, MG, Brazil

[2] Univ Fed Minas Gerais, Inst Ciencias Biol, Dept Bioquim & Imunol, Belo Horizonte, MG, Brazil

[3] Univ Fed Minas Gerais, Dept Anal Clin & Toxicol, Fac Farm, Belo Horizonte, MG, Brazil

[4] Monash Univ, Sch Clin Sci, Monash Hlth, Rheumatol Grp,Ctr Inflammatory Dis, Clayton, Vic, Australia

[5] Univ Perugia, Dept Med, Pharmacol Sect, Perugia, Italy

来源：

PHARMACOLOGICAL RESEARCH | 2020年 / 158卷

关键词：

GILZ; Macrophage reprogramming; Efferocytosis; Resolution of inflammation; NF-KAPPA-B; GILZ; INFLAMMATION; RESOLUTION; INHIBITION; ACTIVATION; EFFEROCYTOSIS; NEUTROPHILS; PLASTICITY; MIGRATION;

D O I：

10.1016/j.phrs.2020.104842

中图分类号：

R9 [药学];

学科分类号：

1007 ;

摘要：

Macrophages are professional phagocytes that display remarkable plasticity, with a range of phenotypes that can be broadly characterized by the M1/M2 dichotomy. Glucocorticoid (GC)-induced leucine zipper (GILZ) is a protein known to mediate anti-inflammatory and some pro-resolving actions, including as neutrophil apoptosis. However, the role of GILZ in key macrophage function is not well understood. Here, we investigated the role of GILZ on macrophage reprogramming and efferocytosis. Using murine bone-marrow-derived macrophages (BMDMs), we found that GILZ was expressed in naive BMDMs and exhibited increased expression in M2-like macrophages (IL4-differentiated). M1-like macrophages (IFN/LPS-differentiated) from GILZ(-/-) mice showed higher expression of the M1 markers CD86, MHC class II, iNOS, IL-6 and TNF-alpha, associated with increased levels of phosphorylated STAT1 and lower IL-10 levels, compared to M1-differentiated cells from WT mice. There were no changes in the M2 markers CD206 and arginase-1 in macrophages from GILZ(-/-) mice differentiated with IL-4, compared to cells from WT animals. Treatment of M1-like macrophages with TAT-GILZ, a cell-permeable GILZ fusion protein, decreased the levels of CD86 and MHC class II in M1-like macrophages without modifying CD206 levels in M2-like macrophages. In line with the in vitro data, increased numbers of M1-like macrophages were found into the pleural cavity of GILZ(-/-) mice after LPS-injection, compared to WT mice. Moreover, efferocytosis was defective in the context of GILZ deficiency, both in vitro and in vivo. Conversely, treatment of LPS-injected mice with TAT-GILZ promoted inflammation resolution, associated with lower numbers of M1-like macrophages and increased efferocytosis. Collectively, these data indicate that GILZ is a regulator of important macrophage functions, contributing to macrophage reprogramming and efferocytosis, both key steps for the resolution of inflammation.

引用

页数：12

共 61 条

[1] Resolution of inflammation: Mechanisms and opportunity for drug development [J].